Why are obese people starving?

Why do obese people display symptoms of starvation? ( increased hunger, increased food intake, decreased locomotor activity, decreased fertility )

Clearly something is amiss, If Joe has 5 million dollar's in his bank account, would you expect him to display behaviour of poverty? Ofcourse not, if he did display such behaviour, you would think that either he was mentally impaired ( read: low "will power" in the case of obesity ) , or , that there was some kind of catch, some kind of key missing information that you wasn't aware of.

Like maybe, the bank has a daily withdrawal limit on Joe's account of, lets say, 5 dollars.

Bingo!

Suddenly it becomes obvious why Joe is behaving the way he is. Although he has loads of money in the bank, there are rules and regulations in place that only allow him to use $150 dollars per month. Thats poverty!

In a similar fashion, it is probably a mystery as to why obese people display starvation symptoms, until you measure their AgRP levels that is. ( 1 ) Obese people have increased levels of this protein, which is a potent orexin. So just like Joe, who is in poverty because the bank is blocking access to his money, obese people are starving because the AgRP is blocking access to their energy expenditure.

BTW, AgRP is also increased in anorexia nervosa ( 2 ), so increased levels of AgRP is a sign of starvation and emaciation.

OK, so just how potent is AgRP anyway?

Actually, there is evidence that AgRP rivals that of leptin in potency. ( 3 ) We all know the ob/ob mouse, it is one that does not produce any leptin, and thus its body *thinks* that it is starving and has like zero fat mass. But what happens if you take an ob/ob mouse and also destroy its AgRP neurons???

It turns into a normal mouse!!!!! Its bodyweight becomes normal like wild-type mice and its fertility is returned to normal. Wow! So what does this mean, does leptin work by AgRP?

Well no, not quite, as destruction of leptin receptors in AgRP neurons produces no discernible change in phenotype, but all this really means is that leptin doesnt work to directly influence AgRP itself, and that it is more likely their paths cross further down the metabolic highway.

Here are some configurations to think about.......

normal AgRP + normal leptin = normal
normal AgRP + no leptin = obesity
no AgRP + no leptin = normal*
no AgRP + normal leptin = death ( through starvation and hypothermia )

*There appears to be a point of no return, as severely obese and older ob/ob mice that have thier AgRP neurons destroyed do not survive and die of hypothermia. This can be resolved by injection of norepinephrine, indeed, sympathetic nervous system outflow from the brain regulates lipolysis and body temperature via norepinephrine action on fat cells.

Remember that the primary function of AgRP is to block the MC4R. And as we saw in the previous post, activation of MC4R is required for weight loss. This implies that part of achieving successful weight loss is a reduction in AgRP.

Even metformin may work by reducing AgRP ( 4 ). The only question that remains is, what is the exact function of leptin? Clearly it is intimately involved in fertility, but what is the exact mechanism and pathway?!